Wnt is coming: A role for serum Wnt2 and 4 in fibrotic remodeling following acute myocardial infarction

Myocardial infarction (MI) remains a common and morbid manifestation of cardiovascular disease, and principally occurs following atherosclerotic plaque rupture resulting in atherothrombosis and epicardial coronary artery stenosis.1Virani S.S. Alonso A. Aparicio H.J. et al.Heart disease and stroke statistics-2021 update a report from the American heart association.Circulation. 2021; : E254-E743https://doi.org/10.1161/CIR.0000000000000950Crossref PubMed Scopus (1021) Google Scholar Following MI, the heart undergoes remodeling characterized by cardiomyocyte death, ventricular hypertrophy/dilation, and excessive deposition of extracellular matrix (ECM), resulting in myocardial fibrosis. In the short term, fibrosis is an appropriate compensatory response, replacing cells lost to necrosis, stabilizing the remaining tissue and preventing myocardial rupture and death. However, following scar maturation, continued collagen production increases tensile strength and reduces ventricular compliance. This results in a feedforward loop whereby fibrosis begets a further fibrotic response, culminating in diastolic dysfunction, systolic dysfunction and the development of heart failure (HF), along with providing a substrate for the development of cardiac arrhythmias.2Garoffolo G. Pesce M. Mechanotransduction in the cardiovascular system: from developmental origins to homeostasis and pathology.Cells. 2019; 8: 1607Crossref Scopus (29) Google Scholar As such, understanding key molecular drivers of fibrosis remains essential to restoring a compensated response to injury and improving the prognosis of MI patients. The Wnt protein family are highly-conserved, secreted glycoproteins that bind the Frizzled (Fzd) family of transmembrane receptors. Engagement between Wnt ligands and Fzd receptors prompts the formation of a complex that includes the low-density-lipoprotein-receptor-related proteins (LRP)−5 and LRP6 which can activate canonical Wnt/ꞵ-catenin signalling or numerous ꞵ-catenin-independent cascades. Recent literature has implicated a role for Wnt signalling in promoting cardiac fibrosis through a complex feedback loop that includes transforming growth factor ꞵ (TGFꞵ), ꞵ-catenin, and Akt.3Foulquier S. Daskalopoulos E.P. Lluri G. Hermans K.C.M. Deb A. Blankesteij W.M. WNT signaling in cardiac and vascular disease.Pharmacol Rev. 2018; 70: 68-141Crossref PubMed Scopus (139) Google Scholar In previous work, experimental MI in mice has triggered an upregulation of several Wnt proteins including Wnt2 and Wnt4, however the significance of serum Wnt2 and Wnt4 in acute MI patients and their impact on cardiac fibrosis remains nebulous.4Aisagbonhi O. Rai M. Ryzhov S. Atria N. Feoktistov I. Hatzopoulos A.K. Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition.DMM Dis Model Mech. 2011; 4: 469-483Crossref PubMed Scopus (205) Google Scholar In volume 74 of EBioMedicine, Yin and colleagues5Yin C. Ye Z. Wu J. et al.Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction.EBioMedicine. 2021; 74103745Summary Full Text Full Text PDF Scopus (2) Google Scholar investigated the impact of Wnt2 and Wnt4 on outcomes in acute MI patients and further characterized the physiological and molecular consequences of Wnt2 and Wnt4 modulation with in vivo and in vitro rodent models. In patients following acute MI, Yin et al. demonstrated a positive correlation between both serum Wnt2 and Wnt4 levels and major adverse cardiovascular events defined as hospital readmission for unstable angina or MI, HF, stroke, and all cause death over a 1-year follow-up period. These findings were corroborated in experimental MI induced by left anterior descending artery (LAD) ligation in C57BL/6 male mice, wherein Wnt2 and Wnt4 serum protein levels increased approximately 3-fold 3 days following surgery and were maintained until 28 days post-MI. Interestingly, cardiac Wnt2 and Wnt4 showed a similarly significant increase 3 days post-MI but a decrease to below-baseline levels at day 7, with a recovery to baseline at day 14 and day 28 post-MI. To explore the molecular underpinnings of Wnt2 and Wnt4 action in cardiac cells, Yin and colleagues used genetic or pharmacological means to modulate Wnt signalling constituents in both their experimental MI model and in neonatal rat cardiomyocytes (NRCMs) or neonatal rat cardiac fibroblasts (NRCFs) subjected to hypoxia. Similar to the LAD ligation model, hypoxia prompted the increased expression and secretion of Wnt2 and Wnt4 from both NRCMs and NRCFs with an accompanying increase in expression of ꞵ-catenin, Fzd2, Fzd4, and NF-κB-p65 phosphorylation. Adeno-associated virus 9 (AAV9)-mediated knockdown (KD) of Wnt2/4 in LAD-ligated hearts significantly decreased fibrosis and cardiac dysfunction compared to control MI hearts. Similarly, knockdown of Wnt2/4 in NRCFs decreased pro-fibrotic gene programming in response to hypoxia; Yin and colleagues further conducted elegant genetic (lentivirus-mediated transduction of shRNA or siRNA) or pharmacological (ICG-001, a Wnt/ꞵ-catenin inhibitor, or JSH23 and Neferine, two NF-κB inhibitors) experiments that demonstrated a link between Wnt2 and Wnt4, ꞵ-catenin/NF-κB activation, and pro-fibrotic signalling in cardiac fibroblasts. Yin and colleagues concluded that Wnt2/4 play critical early roles in the activation of the fibrotic response to ischemic injury. Although the experimental models do identify a role for serum Wnt2/4 upregulation early after MI, the interesting lack of correlation in time-dependent changes in cardiac tissue Wnt2/4 expression and serum Wnt2/4 remains unexplained. Furthermore, the reduction in infarct size and fibrosis in response to Wnt2/4 KD may be an epiphenomenon secondary to cell types not explored in this study such as macrophages, which have been implicated in post-MI remodeling via Wnt-dependent mechanisms.6Palevski D. Levin-Kotler L.P. Kain D. et al.Loss of macrophage Wnt secretion improves remodeling and function after myocardial infarction in mice.J Am Heart Assoc. 2017; 6e004387Crossref PubMed Scopus (41) Google Scholar The AAV9-mediated KD of Wnt2/4 does not precisely capitulate the patient scenario because KD of Wnt2/4 was performed 3-weeks prior to MI. Although the clinical data in this study identified elevated Wnt2/4 in the serum of acute MI patients, the exact temporospatial relationships of Wnt2/4 and remodeling remain difficult to determine. Therefore, both in vivo and in vitro experiments wherein KD of Wnt2 and Wnt4 is performed at numerous time points following MI would better link the clinical and rodent data outlined in this work. Yin and colleagues have presented a robust mechanistic framework that outlined a clear link between Wnt2 and Wnt4, ꞵ-catenin/NF-κB activation, and pro-fibrotic signalling in cardiac fibroblasts. The group further demonstrated that Wnt2 and Wnt4 are novel markers of adverse outcomes following an acute MI. This study therefore opens the door to the investigation of Wnt2/4 as both biomarkers and therapeutic targets in HF. Despite significant research attention, therapies targeting fibrosis have not been successful in human clinical studies.7Meagher P.B. Lee X.A. Lee J. et al.Cardiac fibrosis: key role of integrins in cardiac homeostasis and remodeling.Cells. 2021; 10: 770Crossref PubMed Scopus (6) Google Scholar Given that HF remains one of the most expensive diagnoses with a dismal prognosis, the clinical importance of new biomarkers and therapeutic targets as presented in this publication, cannot be overstated. XAL, PBM, and KAC contributed equally to this commentary. The authors declare no conflicts of interest related to this work. XAL is supported by a CIHR Frederick Banting and Charles Best Canada Graduate Scholarship – Doctoral, a Ted Rogers Centre for Heart Research PhD Education Fund Award, a St. Michael's Hospital Research Training Centre Scholarship, the Dr. Albert and Dorris Fields Graduate Scholarship in Cardiovascular Physiology, and an Ontario Graduate Scholarship. PBM is supported by a St. Michael's Hospital Research Training Centre Scholarship, and the Dr. John Hepburn Award. KAC holds the Keenan chair in Research Leadership.

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